Inflammatory bowel disease (IBD) is associated with an exaggerated release of inflammatory lipid mediators [e.g. Pgs, LTB4 and platelet- activating factor (PAF) ] which contribute to the symptoms of IBD, exacerbate tissue damage and prolong the time-course of inflammatory episodes. Despite the importance of these mediators to the pathophysiology of IBD, little is known about the sequence of events involved in their generation, although there is strong evidence in other organ systems and disease states that eicosanoid formation can occur by "transcellular metabolism" of an intermediate of leukotrienes i.e. leukotrieneA4 (LTA4). There is a strong likelihood that significant "cell-cell interaction" and "transcellular metabolism" of LTA4 to LTB4, lipoxins, LTC4 and LTD4 occurs in IBD or activation of mucosal defenses, based on the abundance of inflammatory cells resident in close proximity in the intestinal mucosa. Invading inflammatory cells (neutrophils, eosinophils, macrophages) may further potentiate this cellular communication as well as exacerbate the inflammatory process. This proposal is designed to address the hypothesis that there is profound cellular cooperation in IBD, specifically in the transcellular metabolism of LTA4 to LTB4 or lipoxins. Cellular cooperation may also take the form of "priming", through which this process can be up- regulated by enhancing the activity of the donor or recipient cell type or both (e.g. by PAF, fMLP, LPS, TNF or other cytokines). Conversely, pharmacological agents such as 5-lipoxygenase inhibitor, LTB4 and PAF receptor antagonists may be used to down-regulate this cellular cooperation, by inhibiting 5-lipoxygenase or binding of LTB4 and PAF to their receptors. We hypothesize that cell-cell interaction is enhanced in inflammatory bowel disease by an increase in the number of inflammatory cells in the mucosa as well as in their heightened activity, which may lead to the increased production of novel inflammatory mediators. There are no other investigations as yet which address the role of these autacoids in IBD. In this proposal we focus on eicosanoids metabolism by and in neutrophils and eosinophils during cell-cell interaction with mucosal mast cell, and evaluate the effects of these mediators in the bowel inflammation. By improving our understanding of cellular communication in IBD, as well as potentially identifying novel functions of inhibitors and receptor antagonists we anticipate that this proposal will lead to improved pharmacological strategies in the treatment of IBD.